Tigecycline reduces tumorigenesis in colorectal cancer via inhibition of cell proliferation and modulation of immune response

Ruiz-Malagón, Antonio Jesús; Hidalgo-García, Laura; Rodríguez-Sojo, María Jesús; Molina-Tijeras, José Alberto; García, Féderico; Diez-Echave, Patrícia; Vezza, Teresa; Becerra, Patricia; Marchal, Juan Antonio; Redondo–Cerezo, Eduardo; Hausmann, Martin; Rogler, Gerhard; Garrido-Mesa, José; Rodríguez-Cabezas, Maria Elena; Rodríguez-Nogales, Alba; Gálvez, Júlio

doi:10.1016/j.biopha.2023.114760

Cited by 4 publications

(4 citation statements)

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“…Autophagy has also been related to these apparently paradoxical processes This unexpected result prompted us to gain insight into the mechanisms involved in this process. Cancer cells with higher mitochondrial mass are prone to apoptosis [38]. Consistently, TIG dose-dependently counteracted BTZ-linked increase in mitochondrial mass.…”

Section: Discussionmentioning

confidence: 63%

“…Conversely, it produced little apoptosis in other studies [17,25,32]. When we measured the percentage of apoptotic KMS20 cells after 24 and 48 h of exposure with increasing concentrations of TIG (0-75 µM), following published ranges [32,[35][36][37][38][39], we observed that it rose as TIG concentration augmented. This effect was more patent with higher concentrations, and statistical significance was observed from 20 µM to the maximum concentration tested, 75 µM, after exposure for both 24 and 48 h in KMS20 cells.…”

Section: Btz and Tig Individual Treatments Induce Apoptosis In Kms20 ...mentioning

confidence: 63%

“…To properly interpret this study, we first analyzed the proapoptotic effect of TIG as single treatment. It has been described that TIG induces apoptosis in some cellular models [34][35][36][37][38]. Conversely, it produced little apoptosis in other studies [17,25,32].…”

Section: Btz and Tig Individual Treatments Induce Apoptosis In Kms20 ...mentioning

confidence: 99%

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Tigecycline Opposes Bortezomib Effect on Myeloma Cells Decreasing Mitochondrial Reactive Oxygen Species Production

Ramos-Acosta,

Huerta-Pantoja,

Salazar-Hidalgo

et al. 2024

IJMS

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Multiple myeloma is an incurable plasma cell malignancy. Most patients end up relapsing and developing resistance to antineoplastic drugs, like bortezomib. Antibiotic tigecycline has activity against myeloma. This study analyzed tigecycline and bortezomib combination on cell lines and plasma cells from myeloma patients. Apoptosis, autophagic vesicles, mitochondrial mass, mitochondrial superoxide, cell cycle, and hydrogen peroxide were studied by flow cytometry. In addition, mitochondrial antioxidants and electron transport chain complexes were quantified by reverse transcription real-time PCR (RT-qPCR) or western blot. Cell metabolism and mitochondrial activity were characterized by Seahorse and RT-qPCR. We found that the addition of tigecycline to bortezomib reduces apoptosis in proportion to tigecycline concentration. Supporting this, the combination of both drugs counteracts bortezomib in vitro individual effects on the cell cycle, reduces autophagy and mitophagy markers, and reverts bortezomib-induced increase in mitochondrial superoxide. Changes in mitochondrial homeostasis and MYC upregulation may account for some of these findings. These data not only advise to avoid considering tigecycline and bortezomib combination for treating myeloma, but caution on the potential adverse impact of treating infections with this antibiotic in myeloma patients under bortezomib treatment.

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Section: Discussionmentioning

confidence: 63%

Section: Btz and Tig Individual Treatments Induce Apoptosis In Kms20 ...mentioning

confidence: 63%

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Tigecycline Opposes Bortezomib Effect on Myeloma Cells Decreasing Mitochondrial Reactive Oxygen Species Production

Ramos-Acosta,

Huerta-Pantoja,

Salazar-Hidalgo

et al. 2024

IJMS

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“…Clinical trials investigating the drug alone or in combination with standard therapy involve varied tumors, among which: pancreatic cancer (phase 2, NCT02775695); pleural neoplasm (observational, NCT03465774; interventional, NCT02583282; phase 2, NCT01411202); cutaneous T-cell lymphoma (phase 2, NCT02341209); advanced melanoma, in association with temozolomide and ipilimumab (phase 1, NCT01590082); relapsed NHL (phase 2, NCT02086591); bone metastatic breast cancer, in association with bisphosphonates (NCT01847976); in localized breast cancer and uterine cancer (phase2, NCT02874430) or head and neck cancer (phase 2, NCT03076281), in association with metformin. Tigecycline, a glycylcycline designed to overcome tetracycline resistance was shown to interfere with the generation of CSCs (LGR5⁺CD44⁺) in a colon adenocarcinoma murine model ( Ruiz-Malagón et al, 2023 ). Moreover, tigecycline impacted tumorsphere formation in a number of cancer cell lines, including ER (−) breast, ovarian, lung, prostate, and pancreatic cancers and melanoma ( Lamb et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Metabolic vulnerability of cancer stem cells and their niche

Marrone,

Romano,

Malasomma

et al. 2024

Front. Pharmacol.

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Cancer stem cells (CSC) are the leading cause of the failure of anti-tumor treatments. These aggressive cancer cells are preserved and sustained by adjacent cells forming a specialized microenvironment, termed niche, among which tumor-associated macrophages (TAMs) are critical players. The cycle of tricarboxylic acids, fatty acid oxidation path, and electron transport chain have been proven to play central roles in the development and maintenance of CSCs and TAMs. By improving their oxidative metabolism, cancer cells are able to extract more energy from nutrients, which allows them to survive in nutritionally defective environments. Because mitochondria are crucial bioenergetic hubs and sites of these metabolic pathways, major hopes are posed for drugs targeting mitochondria. A wide range of medications targeting mitochondria, electron transport chain complexes, or oxidative enzymes are currently investigated in phase 1 and phase 2 clinical trials against hard-to-treat tumors. This review article aims to highlight recent literature on the metabolic adaptations of CSCs and their supporting macrophages. A focus is provided on the resistance and dormancy behaviors that give CSCs a selection advantage and quiescence capacity in particularly hostile microenvironments and the role of TAMs in supporting these attitudes. The article also describes medicaments that have demonstrated a robust ability to disrupt core oxidative metabolism in preclinical cancer studies and are currently being tested in clinical trials.

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Regulation of metastatic potential by drug repurposing and mitochondrial targeting in colorectal cancer cells

Mathur,

Srivastava,

Srivastava

et al. 2024

BMC Cancer

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Background Increased mitochondrial activities contributing to cancer cell proliferation, invasion, and metastasis have been reported in different cancers; however, studies on the therapeutic targeting of mitochondria in regulating cell proliferation and invasiveness are limited. Because mitochondria are believed to have evolved through bacterial invasion in mammalian cells, antibiotics could provide an alternative approach to target mitochondria, especially in cancers with increased mitochondrial activities. In this study, we investigated the therapeutic potential of bacteriostatic antibiotics in regulating the growth potential of colorectal cancer (CRC) cells, which differ in their metastatic potential and mitochondrial functions. Methods A combination of viability, cell migration, and spheroid formation assays was used to measure the effect on metastatic potential. The effect on mitochondrial mechanisms was investigated by measuring mitochondrial DNA copy number by qPCR, biogenesis (by qPCR and immunoblotting), and functions by measuring reactive oxygen species, membrane potential, and ATP using standard methods. In addition, the effect on assembly and activities of respiratory chain (RC) complexes was determined using blue native gel electrophoresis and in-gel assays, respectively). Changes in metastatic and cell death signaling were measured by immunoblotting with specific marker proteins and compared between CRC cells. Results Both tigecycline and tetracycline effectively reduced the viability, migration, and spheroid-forming capacity of highly metastatic CRC cells. This increased sensitivity was attributed to reduced mtDNA content, mitochondrial biogenesis, ATP content, membrane potential, and increased oxidative stress. Specifically, complex I assembly and activity were significantly inhibited by these antibiotics in high-metastatic cells. Significant down-regulation in the expression of mitochondrial-mediated survival pathways, such as phospho-AKT, cMYC, phospho-SRC, and phospho-FAK, and upregulation in cell death (apoptosis and autophagy) were observed, which contributed to the enhanced sensitivity of highly metastatic CRC cells toward these antibiotics. In addition, the combined treatment of the CRC chemotherapeutic agent oxaliplatin with tigecycline/tetracycline at physiological concentrations effectively sensitized these cells at early time points. Conclusion Altogether, our study reports that bacterial antibiotics, such as tigecycline and tetracycline, target mitochondrial functions specifically mitochondrial complex I architecture and activity and would be useful in combination with cancer chemotherapeutics for high metastatic conditions.

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Tigecycline reduces tumorigenesis in colorectal cancer via inhibition of cell proliferation and modulation of immune response

Cited by 4 publications

References 58 publications

Tigecycline Opposes Bortezomib Effect on Myeloma Cells Decreasing Mitochondrial Reactive Oxygen Species Production

Tigecycline Opposes Bortezomib Effect on Myeloma Cells Decreasing Mitochondrial Reactive Oxygen Species Production

Metabolic vulnerability of cancer stem cells and their niche

Regulation of metastatic potential by drug repurposing and mitochondrial targeting in colorectal cancer cells

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